Abstract

Glia of the central nervous system (CNS) help to maintain homeostasis in the brain and support efficient neuronal function. Microglia are innate immune cells of the brain that mediate responses to pathogens and injury. They have key roles in phagocytic clearing, surveying the local microenvironment and propagating inflammatory signals. An interruption in homeostasis induces a cascade of conserved adaptive responses in glia. This response involves biochemical, physiological and morphological changes and is associated with the production of cytokines and secondary mediators that influence synaptic plasticity, cognition and behavior. This reorganization of host priorities represents a beneficial response that is normally adaptive but may become maladaptive when the profile of microglia is compromised. For instance, microglia can develop a primed or pro-inflammatory mRNA, protein and morphological profile with aging, traumatic brain injury and neurodegenerative disease. As a result, primed microglia exhibit an exaggerated inflammatory response to secondary and sub-threshold challenges. Consequences of exaggerated inflammatory responses by microglia include the development of cognitive deficits, impaired synaptic plasticity and accelerated neurodegeneration. Moreover, impairments in regulatory systems in these circumstances may make microglia more resistant to negative feedback and important functions of glia can become compromised and dysfunctional. Overall, the purpose of this review is to discuss key concepts of microglial priming and immune-reactivity in the context of aging, traumatic CNS injury and neurodegenerative disease. This article is part of a Special Issue entitled 'Neuroimmunology and Synaptic Function'.

This diagram illustrates that microglia in the healthy brain are surveying their local microenvironment. Microglia become active with immune challenge and secrete cytokines but return to a surveying state with the resolution of the challenge. In the healthy brain, microglial activation is transient, adaptive and beneficial to the host organism. In aging, after TBI or in neurodegenerative disease, there is evidence that microglia develop an altered morphology and primed or immune-reactive phenotype. Compared to the healthy brain, primed microglia have an intermediate morphological profile with increased expression of several inflammatory receptors and mediators. In the rodent models where this priming profile of microglia is detected, immune challenge promotes amplified and prolonged inflammatory responses that are maladaptive. In models of neurodegenerative disease, there is evidence that these events promote chronic and unresolved inflammation.

Microglial Priming and Senescence in the Aged Brain: Two Different Sides of the Same Coin?

This diagram illustrates that microglia in the aged brain have been described as either primed (left side) or senescent (right side). While the two are often considered to be contrasting issues, it is more likely that they are related issues and that it depends on the context in which the function of aged microglia is being evaluated. On one hand, aged microglia have a more inflammatory profile and this is exaggerated after a transient immune challenge (peripheral or central). On the other hand, aged microglia have a reduction in proliferation, motility and ability to clear debris. In both sides of the coin, regulation of these microglia is impaired.

Behavioral and Cognitive Consequences of Exaggerated Response to Secondary Insult

This diagram represents the interactions between the primary insult aging, CNS trauma or disease and the secondary insult (transient immune challenge or traumatic CNS injury). There is clear interaction between these events on the level of neuroinflammation. In each case, the cited references provide evidence for amplified and prolonged neuroinflammation mediated by microglia that is associated with cognitive impairment, behavioral deficits and progressive pathology.

Astrocytes also have a more ‘reactive’ profile with higher GFAP expression after TBI or in neurodegenerative disease. The long-term consequence of this reactive astrocyte profile in the brain is not well understood. One idea that this these altered profiles of astrocytes affects the dynamic interaction with active microglia. In this scenario, astrocytes help to regulate microglia activation. Thus it takes the appropriate interactions between these two glia cells types to make things go right.